A secondary sulfonamido group (-NHSO2R) is prevalent in small organic molecules of pharmacological importance including non-steroidal anti-inflammatory agents. These drugs have benefited from the strategic incorporation of fluorine atom/s or fluorine-containing group/s on the aromatic ring. With these considerations in mind, we synthesised ortho-arylsulfonamidoacetophenone derivatives 2a–f (70–85% yield) substituted with either a fluorine atom or fluorine-containing (-CF3 or -OCF3) group on the benzenesulfonyl moiety. The N-4-(trifluoromethylbenzene)sulfonyl derivative 2e exhibited increased inhibitory activity against COX-1 (IC50 = 3.14 ± 0.001 µM) and strongly so against COX-2 (IC50 = 0.84 ± 0.002 µM) activity compared to celecoxib (IC50 = 8.17 ± 0.006 µM and 2.78 ± 0.003 µM, respectively). This compound was also found to be the most active against VEGFR-2 tyrosine kinase activity with an IC50 value of 5.73 ± 0.012 µM compared to nintedanib (IC50 = 2.10 ± 0.014 µM) and staurosporine (IC50 = 3.54 ± 0.025 µM). Molecular docking predicted the fluorine atom/s, phenylacetyl and benzenesulfonamido groups to engage in increased hydrophilic and hydrophobic bonding interactions with the amino acid residues in the active sites of these enzymes consistent with the design strategy.